Exploration of 2-phenylquinoline-4-carboxamide linked benzene sulfonamide derivatives as isoform selective inhibitors of transmembrane human carbonic anhydrases

Swain, Baijayantimala; Sahoo, Santosh Kumar; Singh, Priti; Angeli, Andrea; Yaddanapudi, Venkata Madhavi; Supuran, Claudiu T.; Arifuddin, Mohammed

doi:10.1016/j.ejmech.2022.114247

Cited by 11 publications

(10 citation statements)

References 24 publications

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“…All of the compounds exhibited adequate inhibition toward tumor-associated isoforms hCA-IX and hCA-XII, with the inhibition constant ranging from 0.17 to 14.58 μM. Among the synthesized derivatives, compound 11 with an IC 50 value of 0.17 ± 0.05 μM was found to be a more potent hCA-IX inhibitor due to the electron-donating effect of the methyl substituent at the m- position on ring A and sulfonamide substituents at the o- and p -positions while the chloro group at the m -position of ring B . Compound 18 exhibited inhibition with an IC 50 value of 0.21 ± 0.09 μM due to the presence of a methoxy substituent on ring A and a free carboxylic acidic group at the para position on ring B .…”

Section: Resultsmentioning

confidence: 99%

“…Among the synthesized derivatives, compound 11 with an IC 50 value of 0.17 ± 0.05 μM was found to be a more potent hCA-IX inhibitor due to the electron-donating effect of the methyl substituent at the m- position on ring A and sulfonamide substituents at the o- and p -positions while the chloro group at the m -position of ring B . 30 Compound 18 exhibited inhibition with an IC 50 value of 0.21 ± 0.09 μM due to the presence of a methoxy substituent on ring A and a free carboxylic acidic group at the para position on ring B . Compounds 10 , 13 , 17, 19, 24, 22, 25 , and 26 exhibited good inhibition with IC 50 values of 14.58, 10.36, 1.71, 1.01, 1.25, 4.93, 9.76, and 1.28 μM, respectively, compared with that of the standard inhibitor.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Evaluation of Amide and Thiourea Derivatives as Carbonic Anhydrase (CA) Inhibitors

et al. 2022

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Series of sulfonamide-substituted amide (9–11), benzamide (12–15), and 1,3-disubstituted thiourea (17–26) derivatives were synthesized from a common precursor, i.e., substituted benzoyl chlorides. Structures of all of the synthesized compounds were characterized by spectroscopic techniques (1H nuclear magnetic resonance (NMR),13C NMR, and Fourier transform infrared spectroscopy (FTIR)). All of the amide (9–15) and thiourea (17–26) derivatives were screened against human carbonic anhydrases, hCA-II, hCA IX, and hCA-XII. Sulfonamide-substituted amides 9, 11, and 12 were found to be excellent selective inhibitors with IC50 values of 0.18 ± 0.05, 0.17 ± 0.05, and 0.58 ± 0.05 μM against hCA II, hCA IX, and hCA XII, respectively. Compound 9 was found to be highly selective for hCA II and about 6-fold more potent as compared to the standard antagonist, acetazolamide. Safe toxicity profiling of the most potent and selective compounds was determined against normal BHK-21 and HEK-293 T cells. Molecular docking studies were performed, which described the type of interactions between the synthesized compounds and enzyme proteins. In addition, in silico absorption, distribution, metabolism, and excretion (ADME) studies were performed, which showed that all of the synthesized molecules fulfilled the druggability criteria.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Amide and Thiourea Derivatives as Carbonic Anhydrase (CA) Inhibitors

et al. 2022

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“…The commercially available isatin ( A ) was used as the starting material for the compound synthesis. Intermediates B1-B29 were obtained by the coupling of isatin with substituted acetophenone through the Pfitzinger reaction ( Swain et al, 2022 ). After that, key intermediates C1-C28 were derived by the condensation of the intermediates B1-B29 with 4-(piperazine-1-yl) methyl benzoate ( Yamada et al, 2017 ).…”

Section: Chemistrymentioning

confidence: 99%

Discovery of 2-Phenylquinoline-4-Carboxylic Acid Derivatives as Novel Histone Deacetylase Inhibitors

et al. 2022

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Inhibition of histone deacetylases (HDACs) has been extensively studied in the development of anticancer drugs. In the discovery of potent HDAC inhibitors with novel structures, the 2-substituted phenylquinoline-4-carboxylic acid group was introduced to the cap moiety of HDAC inhibitors. In total, 30 compounds were synthesized with hydroxamic acid or hydrazide zinc-binding groups. In the enzyme inhibitory test, active compound D28 and its analog D29 exhibited significant HDAC3 selectivity against HDAC1, 2, 3, and 6. However, compared with D28, the hydrazide-bearing compounds (D29 and D30) with remarkably improved enzyme inhibitory activities did not exhibit significant antiproliferative potency in the in vitro anticancer study. Further K562 cell-based mechanistic results revealed that induction of G2/M cell cycle arrest and promotion of apoptosis make important contributions to the anticancer effects of molecule D28. Collectively, an HDAC3 selective inhibitor (D28) with potent in vitro anticancer activity was developed as a lead compound for the treatment of cancer.

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“…Primary sulfonamides were discovered as CA inhibitors (CAIs) in the ‘40s of the last century, and a majority of the drugs approved for clinical use in the following decades (antiglaucoma agents, antiepileptics, and diuretics) belonged to primary sulfonamides or to their isosteres such as sulfamates and sulfamides. − The main drawback of the first generation of CAIs was the lack of isoform selectivity. − A decade ago and following years, several discoveries were made resulting in a new generation of CAIs belonging to coumarins and sulfocoumarins and their bioisosteres which showed significant isoform-selective inhibition profiles as demonstrated in numerous studies. − This is because those compounds possess a different inhibition mechanism compared to the sulfonamides, which coordinate to the zinc ion from the CA active site as anions. − Recently, the so-called tail approach also has proven to give considerable inhibition selectivity among CA isoforms in case of primary sulfonamides. − This approach using a sulfonamide moiety as a warhead and tropo-flexible tail able to effectively adapt in the cavity of active center was employed in this study.…”

Section: Introductionmentioning

confidence: 99%

Atropo/Tropo Flexibility: A Tool for Design and Synthesis of Self-Adaptable Inhibitors of Carbonic Anhydrases and Their Antiproliferative Effect

et al. 2023

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Here, we report for the first time a series of sulfonamide derivatives with scaffolds bearing flexible moieties, namely, rotamers or tropoisomers capable of adapting their geometry in the active center of enzymes thus being effective and selective carbonic anhydrase (CAs, EC 4.2.1.1) enzyme inhibitors. All compounds exhibited effective in vitro inhibition activity toward the main hCA isoforms related to cancer (i.e., hCA II, hCA IX, and hCA XII with K I values in the low nanomolar range). Three selected compounds showed a great cytotoxic effect on cancer cell lines ex vivo. X-ray crystallographic experiments assessed the binding modes of compound 35 with active centers of hCA IX and hCA XII.

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Exploration of 2-phenylquinoline-4-carboxamide linked benzene sulfonamide derivatives as isoform selective inhibitors of transmembrane human carbonic anhydrases

Cited by 11 publications

References 24 publications

Synthesis and Evaluation of Amide and Thiourea Derivatives as Carbonic Anhydrase (CA) Inhibitors

Synthesis and Evaluation of Amide and Thiourea Derivatives as Carbonic Anhydrase (CA) Inhibitors

Discovery of 2-Phenylquinoline-4-Carboxylic Acid Derivatives as Novel Histone Deacetylase Inhibitors

Atropo/Tropo Flexibility: A Tool for Design and Synthesis of Self-Adaptable Inhibitors of Carbonic Anhydrases and Their Antiproliferative Effect

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